Research IndicatorsGraph generated 15 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MACC1 (cancer-related)
Zhang T, Liu W, Zeng XC, et al.Down-regulation of microRNA-338-3p promoted angiogenesis in hepatocellular carcinoma.
Biomed Pharmacother. 2016; 84:583-591 [PubMed
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miRNAs are involved in substantial biological passways, including tumorigenesis, cancer development and progression. Angiogenesis plays a vital role in the progression of hepatocellular carcinoma (HCC), and VEGF is closely associated with the angiogenesis. However, the molecular mechanism of miRNAs in regulation tumorigenesis of HCC remains to be investigated. In the present research, we confirmed that miR-338-3p was suppressed both in HCC tissues and HCC cell lines. Then the tube formation, transwell and Chorioallantoic membrane (CAM) assay were carried out, such indicated that down-regulation of miR-338-3p can sharply increased, while up-regulation drastically suppressed angiogenesis of HCC cells in vitro. Moreover, MACC1 is predicted to be a target of miR-338-3p and we checked the prediction through luciferase assay. And then, our research showed that negative correlation existed between miR-338-3p and MACC1, β-catenin and VEGF that has been reported participated in cancer behavior in HCC cell lines. Subsequently, our assays illustrated that suppression miR-338-3p can up-regulate MACC1, β-catenin and VEGF expression of HCC cells. In conclusion, our research discovered that miR-338-3p can contribute to HCC angiogenesis by targeting MACC1, β-catenin and VEGF.
Wang G, Gu J, Gao YMicroRNA target for MACC1 and CYR61 to inhibit tumor growth in mice with colorectal cancer.
Tumour Biol. 2016; 37(10):13983-13993 [PubMed
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Cysteine-rich protein 61 (CYR61) and metastasis associated in colon cancer (MACC1) protein promoted human colorectal cancer (CRC) cell metastasis and closely related to the patient's prognosis in colorectal cancer. The purpose of this article is to investigate whether CYR61 and MACC1 can serve as dual potential targets for gene therapy of human CRC. In this study, microRNA (miRNA) targeting for both CYR61 and MACC1 was used to investigate the mechanism and therapeutic effects for CRC cells and mice with CRC. We observed that silencing miRNA for CYR61 and MACC1 inhibited the epithelial-mesenchymal transition (EMT) process, and co-treatment strengthened this effect. MTT assay showed that the growth of colorectal tumor cells was decreased due to miRNA treatment. Apoptosis assay revealed that miRNA for CYR61 and MACC1 promoted CRC cells apoptotic. The animals' study results showed that the expression levels of CYR61 and MACC1 were significantly decreased after miRNA-100 and miRNA-143 treatment, respectively. The expression levels of apoptosis-promoting protein were increased significantly after treatment with miRNA-100 and miRNA-143, which suggested that both miRNA-100 and miRNA-143 may induce apoptosis by mitochondria-dependent pathway. In addition, metastasis and invasion assays showed that miRNA-100 and miRNA-143 treatment inhibited obviously migratory and invasive abilities of CRC cells. Furthermore, our data also showed that the tumor growth was significantly inhibited and survival rate of tumor-bearing mice was greatly improved by common treatments of miRNA-100 and miRNA-143. In conclusion, the abilities of apoptosis, metastasis, and invasion in CRC tumor cells were significantly suppressed by miRNA-100 and miRNA-143 targeting CYR61 and MACC1, respectively. As a result, CYR61 and MACC1 may serve as potential targets for gene therapy in human CRC treatments.
Ding Y, Li X, Hong D, et al.Silence of MACC1 decreases cell migration and invasion in human malignant melanoma through inhibiting the EMT.
Biosci Trends. 2016; 10(4):258-64 [PubMed
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Metastasis-associated colon cancer 1 (MACC1) has been demonstrated to promote metastasis of several cancers via regulating epithelial-mesenchymal transition (EMT). However, its biological behavior in human malignant melanoma remains unclear. In this study, MACC1 downregulation was established in two melanoma cell lines (A375 and G361 cells) using RNA interference, as confirmed by quantitative real time PCR (qRT-PCR) and Western blot analysis. Subsequently, we investigated the effects of MACC1 silencing on cell mobility, migration and invasion using scratch wound and Transwell assays. Our results indicated that knockdown of MACC1 significantly suppressed cell migration and invasion ability of both melanoma cell lines. Moreover, downregulation of MACC1 upregulated E-cadherin, N-cadherin and Vimentin, as confirmed by qRT-PCR, Western blot and immunofluorescent Staining analysis. These findings suggest MACC1 might serve as a new molecular target for the treatment of melanoma by a novel mechanism underlying the metastasis of melanoma cells.
BACKGROUND Human brain glioma is the most common endocranial tumor; its mortality and morbidity are very high. The objective of this study was to determine whether miR-338-3p can regulate malignant biological behaviors of glioma cells by targeted silencing of MACC1. MATERIAL AND METHODS The expression of miR-338-3p was detected by quantitative real-time PCR in brain glioma tissues and cell lines. Bioinformatics software was used to predict some potential target genes of miR-338-3p. Luciferase activities assay was used to verify the combination between target genes and miR-338-3p. And MACC1 protein expression was detected by Western blot. The apoptosis and proliferation ability were analyzed by MTT and flow cytometry assay. RESULTS Compared with normal brain tissues and cells, miR-338-3p in glioma tissues and cell lines was confirmed to be expressed at low levels, and down-regulation of miR-338-3p tended to be correlated with worse histological grade. Up-regulation of miR-338-3p promoted apoptosis and sharply inhibited cell proliferation ability of U251 and U87 cells. The luciferase activities assay, biotin-avidin pull-down assay, and western blot analysis verified that MACC1 was a specific target gene of miR-338-3p. Subsequent experiments found that up-regulation of MACC1 significantly inhibited the apoptosis and increased the cell proliferation ability of U251 and U87 cells. The regulation effects of miR-338-3p on malignant biological behaviors of glioma cells can be partly reversed by up-regulation of MACC1. CONCLUSIONS Down-regulation of miR-338-3p was an independent prognostic biomarker associated with poor prognosis in glioma patients; miR-338-3p acted as a tumor-suppressing gene whose silencing can inhibit malignant biological behaviors of glioma cells. MACC1 was a specific target gene of miR-338-3p, which regulates malignant biological behaviors of glioma cells partly through directly silencing MACC1 expression.
The neurotransmitter acetylcholine (ACh) promotes the growth and metastasis of several cancers via its M3 muscarinic receptor (M3R). Metastasis-associated in colon cancer-1 (MACC1) is an oncogene that is overexpressed in gastric cancer (GC) and plays an important role in GC progression, though it is unclear how MACC1 activity is regulated in GC. In this study, we demonstrated that ACh acts via M3Rs to promote GC cell invasion and migration as well as expression of several markers of epithelial-mesenchymal transition (EMT). The M3R antagonist darifenacin inhibited GC cell activity in both the presence and absence of exogenous ACh, suggesting GC cells secrete endogenous ACh, which then acts in an autocrine fashion to promote GC cell migration/invasion. ACh up-regulated MACC1 in GC cells, and MACC1 knockdown using siRNA attenuated the effects of ACh on GC cells. AMP-activated protein kinase (AMPK) served as an intermediate signal between ACh and MACC1. These findings suggest that ACh acts via a M3R/AMPK/MACC1 signaling pathway to promote GC cell invasion/migration, which provides insight into the mechanisms underlying GC growth and metastasis and may shed light on new targets for GC treatment.
The consequence of a loss of balance between G-protein activation and deactivation in cancers has been interrogated by studying infrequently occurring mutants of trimeric G-protein α-subunits and GPCRs. Prior studies on members of a newly identified family of non-receptor guanine nucleotide exchange factors (GEFs), GIV/Girdin, Daple, NUCB1 and NUCB2 have revealed that GPCR-independent hyperactivation of trimeric G proteins can fuel metastatic progression in a variety of cancers. Here we report that elevated expression of each GEF in circulating tumor cells (CTCs) isolated from the peripheral circulation of patients with metastatic colorectal cancer is associated with a shorter progression-free survival (PFS). The GEFs were stronger prognostic markers than two other markers of cancer progression, S100A4 and MACC1, and clustering of all GEFs together improved the prognostic accuracy of the individual family members; PFS was significantly lower in the high-GEFs versus the low-GEFs groups [H.R = 5, 20 (95% CI; 2,15-12,57)]. Because nucleotide exchange is the rate-limiting step in cyclical activation of G-proteins, the poor prognosis conferred by these GEFs in CTCs implies that hyperactivation of G-protein signaling by these GEFs is an important event during metastatic progression, and may be more frequently encountered than mutations in G-proteins and/or GPCRs.
Zhang R, Shi H, Ren F, et al.Knockdown of MACC1 expression increases cisplatin sensitivity in cisplatin-resistant epithelial ovarian cancer cells.
Oncol Rep. 2016; 35(4):2466-72 [PubMed
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Abnormal expression of metastasis-associated in colon cancer 1 (MACC1) was found to be closely associated with several types of malignant tumors. The present study aimed to verify the relationship between MACC1 and cisplatin resistance in ovarian cancer cells and the possible mechanisms, which was implemented by inhibition of the expression of MACC1 in cisplatin-resistant human ovarian cancer cell lines A2780/DDP and COC1/DDP. MACC1 shRNA eukaryotic plasmids and negative control plasmids were transfected into A2780/DDP and COC1/DDP cells, respectively, while A2780/DDP and COC1/DDP cells were used as blank controls. Western blotting and sqRT-PCR were used to detect the expression of MACC1 in the different cell groups. Different concentrations of cispaltin (0, 10, 20, 30, 40, 50 and 60 µmol/l) were used to treat the cell groups, respectively, and then the chemosensitivity of cisplatin and cell apoptosis were examined by MTT and flow cytometry, respectively. The activity of caspase-3 was determined by spectrophotometry. Expression levels of p-ERK1/2, permeability glycoprotein (P-gp), B-cell lymphoma 2 (Bcl-2), Bcl-XL, Bax and Bad protein were detected in the different ovarian cancer cells by western blotting. After MACC1 knockdown, the chemosensitivity of cisplatin in the ovarian cancer cells was enhanced, and the cell growth inhibition and apoptosis rates were increased. The expression levels of Bax and Bad were upregulated, the activity of caspase-3 was increased, while the expression levels of p-ERK1/2, P-gp, Bcl-2 and Bcl-XL were downregulated as a result of MACC1 inhibition. These results indicate that inhibition of MACC1 improves the chemosensitivity of cisplatin in epithelial ovarian cancer cells, through the regulation of the ERK1/2 signaling pathway on P-gp and its downstream apoptosis proteins.
Hepatocellular carcinoma (HCC) is a primary cancer of the liver that is predominant in developing countries and is responsible for nearly 600000 deaths each year worldwide. Similar to many other tumors, the development of HCC must be understood as a multistep process involving the accumulation of genetic and epigenetic alterations in regulatory genes, leading to the activation of oncogenes and the inactivation or loss of tumor suppressor genes. Extensive research over the past decade has identified a number of molecular biomarkers, including aberrant expression of HCC-related genes and microRNAs. The challenge facing HCC research and clinical care at this time is to address the heterogeneity and complexity of these genetic and epigenetic alterations and to use this information to direct rational diagnosis and treatment strategies. The multikinase inhibitor sorafenib was the first molecularly targeted drug for HCC to show some extent of survival benefits in patients with advanced tumors. Although the results obtained using sorafenib support the importance of molecular therapies in the treatment of HCC, there is still room for improvement. In addition, no molecular markers for drug sensitivity, recurrence and prognosis are currently clinically available. In this review, we provide an overview of recently published articles addressing HCC-related genes and microRNAs to update what is currently known regarding genetic and epigenetic aspects of the pathogenesis of HCC and propose novel promising candidates for use as diagnostic and therapeutic targets in HCC.
The purpose of this article is to research on whether MACC1 can serve as a potential target for gene therapy of human bladder urothelial carcinoma (BUC). In this study, the expression of MACC1 gene was knocked down by RNA interference (RNAi) in the T24 cell (human BUC cell). The transcription level of MACC1 was detected by RT-PCR. Activities of MACC1, caspase-3, caspase-8, Bax and Met (mesenchymal-epithelial transition factor) protein were measured by Western blot. The cell proliferation and apoptosis were detected by MTT and flow cytometry. The cell's invasion ability was performed on Matrigel transwell assay. We also detect MMP2 (metalloproteinase-2) proteins by ELISA. The results showed that the level of MACC1 mRNA and protein was significantly reduced after RNAi. MTT assay showed that the proliferation of T24 cell was decreased due to RNA interference. Apoptosis studies also showed that MACC1 gene interference in T24 loses its anti-apoptotic effects. The expression of apoptosis proteins (Caspase-3, Caspase-8 and Bax) increased significantly due to the MACC1 RNAi. The level of Met protein was down-regulated obviously due to RNAi. Transwell assay showed that invasion abilities of T24 cells were reduced obviously due to MACC1 RNAi. Further studies showed that the secretion of MMP-2 was reduced by RNAi. It can conclude that the ability of proliferation and invasion in T24 cells can be inhibited by RNAi-targeting MACC1. As a result, MACC1 can serve as a potential target for gene therapy of human bladder urothelial carcinoma.
Zhou X, Xu CJ, Wang JX, et al.Metastasis-Associated in Colon Cancer-1 Associates With Poor Prognosis and Promotes Cell Invasion and Angiogenesis in Human Cervical Cancer.
Int J Gynecol Cancer. 2015; 25(8):1353-63 [PubMed
] Free Access to Full Article Related Publications
OBJECTIVE: The aim of this study is to investigate the clinicopathologic significance and potential role of metastasis-associated in colon cancer-1 (MACC1) in the progression of cervical cancer.
METHODS: MACC1 expression was examined in cervical cancer cell lines, 6 matched cervical cancer tissues, and adjacent noncancerous tissues using Western blotting and real-time reverse transcriptase polymerase chain reaction. MACC1 protein expression and localization were determined in 181 paraffin-embedded archived cervical cancer samples using immunohistochemistry. Statistical analyses were applied to evaluate the clinicopathologic significance. The effects of MACC1 on cell migration, invasion, and angiogenesis were examined using migration assay, wound healing assay, 3-dimensional morphogenesis assay, and chicken chorioallantoic membrane assay. Western blotting was performed to examine the impact of MACC1 on the Akt and nuclear factor κB signaling pathways.
RESULTS: Both protein and messenger RNA levels of MACC1 was up-regulated in cervical cancer cell lines and cervical cancer tissues, as compared with normal tissues. High MACC1 expression was detected in 96 (53%) of 181 of the cervical cancer tissues. In addition, high MACC1 expression correlated significantly with aggressiveness of cervical cancer, including International Federation of Gynecology and Obstetric stage (P = 0.001), pelvic lymph node metastasis (P = 0.004), recurrence (P = 0.037), and poor survival (P = 0.001). Moreover, enforced expression of MACC1 in cervical cancer cell lines significantly enhanced cell migration, invasion, and angiogenesis. Conversely, knockdown of MACC1 caused an inhibition of cell migration, invasion, and angiogenesis. Up-regulation of MACC1 increased, but knockdown of MACC1 decreased the expression of matrix metalloproteinase-2 and matrix metalloproteinase-9. Furthermore, enforced expression of MACC1 could enhance, but knockdown of MACC1 could reduce AKT and nuclear factor κB pathway activity.
CONCLUSIONS: Our findings suggest that MACC1 protein, as a valuable marker of cervical cancer prognosis, plays an important role in the progression of human cervical cancer cells.
BACKGROUND: Epithelial cells in malignant conditions release DNA into the extracellular compartment. Cell free DNA of tumor origin may act as a ligand of DNA sensing mechanisms and mediate changes in epithelial-stromal interactions.
AIMS: To evaluate and compare the potential autocrine and paracrine regulatory effect of normal and malignant epithelial cell-related DNA on TLR9 and STING mediated pathways in HT-29 human colorectal adenocarcinoma cells and normal fibroblasts.
MATERIALS AND METHODS: DNA isolated from normal and tumorous colonic epithelia of fresh frozen surgically removed tissue samples was used for 24 and 6 hour treatment of HT-29 colon carcinoma and HDF-α fibroblast cells. Whole genome mRNA expression analysis and qRT-PCR was performed for the elements/members of TLR9 signaling pathway. Immunocytochemistry was performed for epithelial markers (i.e. CK20 and E-cadherin), DNA methyltransferase 3a (DNMT3a) and NFκB (for treated HDFα cells).
RESULTS: Administration of tumor derived DNA on HT29 cells resulted in significant (p<0.05) mRNA level alteration in 118 genes (logFc≥1, p≤0.05), including overexpression of metallothionein genes (i.e. MT1H, MT1X, MT1P2, MT2A), metastasis-associated genes (i.e. TACSTD2, MACC1, MALAT1), tumor biomarker (CEACAM5), metabolic genes (i.e. INSIG1, LIPG), messenger molecule genes (i.e. DAPP, CREB3L2). Increased protein levels of CK20, E-cadherin, and DNMT3a was observed after tumor DNA treatment in HT-29 cells. Healthy DNA treatment affected mRNA expression of 613 genes (logFc≥1, p≤0.05), including increased expression of key adaptor molecules of TLR9 pathway (e.g. MYD88, IRAK2, NFκB, IL8, IL-1β), STING pathway (ADAR, IRF7, CXCL10, CASP1) and the FGF2 gene.
CONCLUSIONS: DNA from tumorous colon epithelium, but not from the normal epithelial cells acts as a pro-metastatic factor to HT-29 cells through the overexpression of pro-metastatic genes through TLR9/MYD88 independent pathway. In contrast, DNA derived from healthy colonic epithelium induced TLR9 and STING signaling pathway in normal fibroblasts.
Metastasis associated in colon cancer 1 (MACC1), a newly identified oncogene, has been associated with poor survival of cancer patients by multiple studies. However, the prognostic value of MACC1 in digestive system neoplasms needs systematic evidence to verify. Therefore, we aimed to provide further evidence on this topic by systematic review and meta-analysis. Literature search was conducted in multiple databases and eligible studies analyzing survival data and MACC1 expression were included for meta-analysis. Hazard ratio (HR) for clinical outcome was chosen as an effect measure of interest. According to our inclusion criteria, 18 studies with a total of 2,948 patients were identified. Pooled HRs indicated that high MACC1 expression significantly correlates with poorer OS in patients with digestive system neoplasms (HR = 1.94; 95% CI: 1.49-2.53) as well as poorer relapse-free survival (HR = 1.94, 95% CI: 1.33-2.82). The results of subgroup studies categorized by methodology, anatomic structure, and cancer subtype for pooled OS were all consistent with the overall pooled HR for OS as well. No publication bias was detected according to test of funnel plot asymmetry and Egger's test. In conclusion, high MACC1 expression may serve as a prognostic biomarker to guide individualized management in clinical practice for digestive system neoplasms.
Sun L, Li G, Dai B, et al.Silence of MACC1 expression by RNA interference inhibits proliferation, invasion and metastasis, and promotes apoptosis in U251 human malignant glioma cells.
Mol Med Rep. 2015; 12(3):3423-31 [PubMed
] Free Access to Full Article Related Publications
The overexpression of metastasis‑associated in colon cancer 1 (MACC1) has been demonstrated not only in colon cancer, but also in various other types of cancer. Gliomas are the most common type of intracranial tumors, and recent studies have reported MACC1 to be involved in human glioma progression. The present study aimed to investigate the effects of MACC1 expression silencing in glioma cells using RNA interference, in order to determine the underlying biological mechanisms of glioma progression, including proliferation, apoptosis, invasion and metastasis. The expression levels of MACC1 were determined in various types of U251 glioma cells using western blot analyses. MACC1‑specific short hairpin RNA (shRNA) was used to silence the expression of MACC1 in the U251 cells. The results obtained following MACC1 silencing demonstrated a significant inhibition of cell proliferation, invasion and migration, as well as a marked enhancement of apoptosis. MACC1 shRNA‑induced inhibition of cell proliferation was observed by colony forming and MTT assays, and cell apoptosis was measured using flow cytometry and Hoechst staining. In addition, inhibition of cell invasion and migration was assessed using wound healing and transwell assays. Western blotting and fluorescence‑activated cell sorting (FACS) revealed a G0/G1 phase cell cycle arrest regulated by cyclins D1 and E; cell apoptosis regulated by caspase‑3; and cell invasion and migration regulated by matrix metalloproteinases 2 and 9, respectively. The present study demonstrated that the expression levels of MACC1 were significantly correlated with the biological processes underlying glioma cell proliferation, invasion and metastasis. Therefore, MACC1 may serve as a promising novel therapeutic target in human glioma. Notably, the inhibition of MACC1 expression by shRNA may prove to be an effective genetic therapeutic strategy for glioma treatment.
Lederer A, Herrmann P, Seehofer D, et al.Metastasis-associated in colon cancer 1 is an independent prognostic biomarker for survival in Klatskin tumor patients.
Hepatology. 2015; 62(3):841-50 [PubMed
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UNLABELLED: Curative treatment of intrahepatic cholangiocarcinoma (ICC) and hilar cholangiocarcinoma (Klatskin tumors) is limited to surgical resection or orthotopic liver transplantation. However, not all patients benefit from a surgical approach and suffer from early tumor recurrence. Response to chemotherapy is generally poor and, until today, no targeted therapy could be established. Metastasis-associated in colon cancer 1 (MACC1) is a recently discovered regulator of the hepatocyte growth factor (HGF)/Met/mitogen-activated protein kinase pathway, which induces proliferation, migration, and invasion in cell culture, as well as metastasis in mice. MACC1 expression shows a significant correlation with Met expression in colon cancer tissue and is highly prognostic for occurrence of distant metastasis and survival in colon cancer patients. Thus, we aimed to measure the expression of MACC1, Met, and HGF messenger RNA in microdissected tumor tissue and corresponding normal liver tissue of 156 patients with Klatskin tumors (n = 76) and ICC (n = 80) using real-time quantitative reverse-transcriptase polymerase chain reaction. We used immunohistochemical staining to validate the results. MACC1 expression in tumor tissue of both tumor entities was significantly higher than in corresponding normal liver tissue (P < 0.001). Klatskin tumor patients with a history of tumor recurrence had significantly higher MACC1 expression than those without tumor recurrence (P = 0.005). Uni- und multivariate survival analysis showed that Klatskin tumor patients with high MACC1 had a significantly shorter overall (OS) and disease-free survival (DFS; P = 0.001 and P < 0.001, respectively). The multivariate analysis confirmed MACC1 to be an independent factor for overall survival in Klatskin tumor patients (hazard ratio: 2.777; 95% confidence interval: 1.389-5.555; P = 0.004).
CONCLUSION: Our study identified MACC1 as a highly prognostic biomarker for OS and DFS in Klatskin tumor patients. MACC1 expression could become an important diagnostic tool and might be a candidate for targeted therapy.
Zhuang H, Zhao MY, Hei KW, et al.Aberrant expression of pim-3 promotes proliferation and migration of ovarian cancer cells.
Asian Pac J Cancer Prev. 2015; 16(8):3325-31 [PubMed
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Pim kinase-3(Pim-3), a member of serine/threonine protein kinases, has been implicated in multiple human cancers and involved in Myc-induced tumorigenesis. However, little is known regarding its expression and biological function in human ovarian cancer. In this study we showed that the clinical significance and biological functions of Pim-3 in ovarian cancer and found that higher Pim-3 mRNA level are detected in ovarian cancer tissues than those in normal ovarian tissues. There are significant correlations between higher Pim-3 expression levels with the FIGO stage, histopathological subtypes, and distant metastasis in ovarian cancer patients. Lentivirus-mediated gene overexpression of Pim-3 significantly promotes the proliferation and migration of SKOV3 cell lines. Furthermore, MACC1 and Pim-3 expression were significantly correlated in human ovarian cancer cells, and overexpression of Pim-3 in ovary cancer cells increased MACC1 mRNA and protein expression. The data indicate that Pim-3 acts as a putative oncogene in ovary cancer and could be a viable diagnostic and therapeutic target for ovarian cancer.
Koelzer VH, Herrmann P, Zlobec I, et al.Heterogeneity analysis of Metastasis Associated in Colon Cancer 1 (MACC1) for survival prognosis of colorectal cancer patients: a retrospective cohort study.
BMC Cancer. 2015; 15:160 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Metastasis of colorectal cancer (CRC) is directly linked to patient survival. We previously identified the novel gene Metastasis Associated in Colon Cancer 1 (MACC1) in CRC and demonstrated its importance as metastasis inducer and prognostic biomarker. Here, we investigate the geographic expression pattern of MACC1 in colorectal adenocarcinoma and tumor buds in correlation with clinicopathological and molecular features for improvement of survival prognosis.
METHODS: We performed geographic MACC1 expression analysis in tumor center, invasive front and tumor buds on whole tissue sections of 187 well-characterized CRCs by immunohistochemistry. MACC1 expression in each geographic zone was analyzed with Mismatch repair (MMR)-status, BRAF/KRAS-mutations and CpG-island methylation.
RESULTS: MACC1 was significantly overexpressed in tumor tissue as compared to normal mucosa (p < 0.001). Within colorectal adenocarcinomas, a significant increase of MACC1 from tumor center to front (p = 0.0012) was detected. MACC1 was highly overexpressed in 55% tumor budding cells. Independent of geographic location, MACC1 predicted advanced pT and pN-stages, high grade tumor budding, venous and lymphatic invasion (p < 0.05). High MACC1 expression at the invasive front was decisive for prediction of metastasis (p = 0.0223) and poor survival (p = 0.0217). The geographic pattern of MACC1 did not correlate with MMR-status, BRAF/KRAS-mutations or CpG-island methylation.
CONCLUSION: MACC1 is differentially expressed in CRC. At the invasive front, MACC1 expression predicts best aggressive clinicopathological features, tumor budding, metastasis formation and poor survival outcome.
BACKGROUND: The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as prognostic biomarker for colorectal cancer (CRC). Here, we aimed at the refinement of risk assessment by separate and combined survival analyses of MACC1 expression with any of the markers KRAS mutated in codon 12 (KRAS G12) or codon 13 (KRAS G13), BRAF V600 mutation and MSI status in a retrospective study of 99 CRC patients with tumors UICC staged I, II and III.
FINDINGS: We showed that only high MACC1 expression (HR: 6.09, 95% CI: 2.50-14.85, P < 0.001) and KRAS G13 mutation (HR: 5.19, 95% CI: 1.06-25.45, P = 0.042) were independent prognostic markers for shorter metastasis-free survival (MFS). Accordingly, Cox regression analysis revealed that patients with high MACC1 expression and KRAS G13 mutation exhibited the worst prognosis (HR: 14.48, 95% CI: 3.37-62.18, P < 0.001). Patients were classified based on their molecular characteristics into four clusters with significant differences in MFS (P = 0.003) by using the SPSS 2-step cluster function and Kaplan-Meier survival analysis.
CONCLUSION: According to our results, patients with high MACC1 expression and mutated KRAS G13 exhibited the highest risk for metachronous metastases formation. Moreover, we demonstrated that the "Traditional pathway" with an intermediate risk for metastasis formation can be further subdivided by assessing MACC1 expression into a low and high risk group with regard to MFS prognosis. This is the first report showing that identification of CRC patients at high risk for metastasis is possible by assessing MACC1 expression in combination with KRAS G13 mutation.
Li Y, Lu Z, Liang Z, et al.Metastasis-associated in colon cancer-1 is associated with poor prognosis in hepatocellular carcinoma, partly by promoting proliferation through enhanced glucose metabolism.
Mol Med Rep. 2015; 12(1):426-34 [PubMed
] Related Publications
Metastasis-associated in colon cancer-1 (MACC1) is a newly identified gene that is involved in the development and progression of hepatocellular carcinoma (HCC), however its investigation has not been comprehensive. In the present study, in vitro techniques, including immunohistochemistry, western blotting, reverse transcription quantitative polymerase chain reaction, metabolic assay, MTT assay, colony formation assay and prognostic analysis were used to confirm the involvement of MACC1 in HCC. Histological examination confirmed that the protein expression of MACC1 was upregulated in HCC and was associated with the hexokinase-2 (HK2) protein, which also indicates a poor prognosis. Knockdown of MACC1 induced the reduction of glycogen consumption and lactate production, which then lead to a marked reduction of proliferation in the MHCC-97H cells. However, the overexpression of MACC1 produced the opposite results in the HepG2 cells. These results suggested that MACC1 leads to a poor prognosis in HCC, partly by promoting proliferation via enhancement in glucose metabolism by HK2. Therefore, this pathway has the potential to become an important therapeutic target in HCC.
Sueta A, Yamamoto Y, Yamamoto-Ibusuki M, et al.Differential role of MACC1 expression and its regulation of the HGF/c‑Met pathway between breast and colorectal cancer.
Int J Oncol. 2015; 46(5):2143-53 [PubMed
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The newly identified gene, metastasis‑associated in colon cancer 1 (MACC1), is suggested to be a transcriptional regulator of c‑Met, leading to cancer progression in colorectal cancer. To date however, little is known of the role of MACC1 in breast cancer. In a series of 300 breast cancer patients, we analyzed the association of MACC1 mRNA and protein expression with breast cancer survival using Cox proportional hazard models. In an in vitro study, we evaluated activities of c‑Met protein after transfection with a MACC1‑harboring plasmid as well as the binding ability of MACC1 to the c‑Met promoter using a chromatin immunoprecipitation (ChIP) assay. In survival analyses, reduced MACC1 expression was associated with patient mortality. MACC1 expression was an independent prognostic factor in multivariate analysis. In the cell lines tested, MACC1 expression was much higher in colorectal than in breast cancer cells. After cells were transfected with MACC1, c‑Met expression was not induced in MCF7 cells, whereas corresponding c‑Met expression was upregulated in SW480 cells. Further, SW480 cells transfected with MACC1 showed enhanced migratory ability, whereas in MDA‑MB‑231 cells, transfection of MACC1 had no impact on this ability. In ChIP assay, the binding of MACC1 to the c‑Met promoter was suggested in SW480 cells, but not in MCF7 cells. In conclusion, our findings provide some novel insights into the role of MACC1 in breast cancer, indicating that it plays different roles in breast and several other cancers. There is a possibility that MACC1 does not modulate the transcriptional role of c‑Met signaling in breast cancer.
Yao Y, Dou C, Lu Z, et al.MACC1 suppresses cell apoptosis in hepatocellular carcinoma by targeting the HGF/c-MET/AKT pathway.
Cell Physiol Biochem. 2015; 35(3):983-96 [PubMed
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BACKGROUND & AIMS: To investigate the expression and prognostic value of MACC1 in patients with HCC and identify the mechanism by which MACC1 inhibits HCC cell apoptosis.
METHODS: MACC1 and p-AKT expression was studied using immunohistochemistry of both HCC tissues and adjacent liver tissues. qRT-PCR and western immunoblotting were used to examine the expression of target genes at the mRNA and protein levels, respectively. The MTT assay was used to assess cell viability, and cell apoptosis was determined by DAPI staining, Annexin V/PI staining and Caspase 3/7 assay. Nude mice were used to perform in vivo experiments.
RESULTS: The overexpression of MACC1 was found in HCC tissues and was correlated with poor postsurgical prognosis. There was a positive relationship between MACC1 and p-AKT expression in HCC tissues. In vitro experiments showed that MACC1 repressed HCC cell apoptosis and promoted cell growth. Knockdown of c-MET abolished the anti-apoptotic function of MACC1. Next, MACC1 was verified to activate PI3K/AKT signaling by sensitizing HGF/c-MET signaling in HCC. MACC1 overexpression enhanced the HGF-driven phosphorylation of BAD, Caspase 9 and FKHRL1 and inhibited their pro-apoptotic functions in HCC cells. Finally, MACC1 was shown to inhibit cell apoptosis and promote HCC growth in vivo.
CONCLUSIONS: This investigation revealed that MACC1 overexpression predicted worse prognosis after liver resection, which was attributed to the repression of HCC cell apoptosis via a molecular mechanism in which MACC1 accelerated the activation of the HGF/c-MET/PI3K/AKT pathway and phosphorylated BAD, Caspase 9 and FKHRL1, ultimately preventing their nuclear translocation and their pro-apoptotic function.
Shang C, Hong Y, Guo Y, et al.Influence of the MACC1 gene on sensitivity to chemotherapy in human U251 glioblastoma cells.
Asian Pac J Cancer Prev. 2015; 16(1):195-9 [PubMed
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BACKGROUND: This study was conducted to determine the influence of MACC1 expression on chemotherapy sensitivity in human U251 glioblastoma cells.
MATERIALS AND METHODS: Expression of the MACC1 gene in 49 cases of human brain glioma was determined by quantitative real-time PCR. Silencing effects of RNA interference on MACC1 was detected by Western-blotting. Flow cytometry methods and methyl thiazolyl tetrazolium assay (MTT) were used to determine the apoptosis and growth inhibitory rates of the U251 cells with MACC1 silencing. before and after treatment with cisplatin (DDP).
RESULTS: MACC1 mRNA in gliomas was up-regulated remarkably, to 158.8% of that in peri-cancerous tissues (P<0.05). The siRNA-MACC1 could inhibit the expression of MACC1 protein significantly (p<0.05), associated with an increase in apoptosis rate from 2.57% to 5.39% in U251 cells and elevation of the growth inhibitory rate from 1.5% to 17.8% (p<0.05 for both). After treatment with DDP at various concentrations (1, 3, 5μg/ml), compared with control U251 cells, the apoptosis rate of MACC1-silenced U251 cells rose from 8.41%, 13.2% and 19.5% to 12.8%, 17.8% and 25.8%; the growth inhibitory rate increased from 16.2%, 19.3% and 24.5% to 23.7%, 28.4% and 36.3%.
CONCLUSIONS: There is a notable relationship between over-expression of MACC1 and the characteristics of glioma cells. Silencing of MACC1 was found to enhance the apoptosis and growth inhibitory rates of U251 glioma cells, and thereby increase their sensitivity to DDP chemotherapy.
Chen L, Wang J, Fu L, et al.Prognostic significance of metastasis associated in colon cancer 1 (MACC1) expression in patients with gallbladder cancer.
J Cancer Res Ther. 2014 Oct-Dec; 10(4):1052-6 [PubMed
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BACKGROUND: The clinical significance of metastasis associated in colon cancer 1 (MACC1), in human gallbladder cancer, is not yet established. This study was performed to assess the expression of MACC1 in benign and malignant gallbladder lesions, and to assess its clinicopathological significance.
MATERIALS AND METHODS: Tissue samples from resected gallbladder cancer (n=70) and cholelithiasis (n=70) were evaluated for MACC1 expression by immunohistochemical staining. Their expression was correlated with different clinicopathological parameters.
RESULTS: Cytoplasmic MACC1 expression was significantly higher (58.6%) in gallbladder cancer than in chronic cholecystitis (27.1%, P<0.001). High MACC1 levels were associated with lymph node metastasis (P<0.05), tumor node metastasis (TNM) stage (P<0.01), and perineural invasion (P<0.01), but not with sex, age, history of gallstones or histological grade (P>0.05). The univariate Kaplan-Meier analysis showed that a positive MACC1 expression was associated with decreased overall survival (P<0.001). The multivariate Cox regression analysis showed that MACC1 expression and the histopathological subtypes were independent risk factors for disease-free survival.
CONCLUSION: The expression of MACC1 might be closely related to carcinogenesis, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma.
Wang Z, Cai M, Weng Y, et al.Circulating MACC1 as a novel diagnostic and prognostic biomarker for nonsmall cell lung cancer.
J Cancer Res Clin Oncol. 2015; 141(8):1353-61 [PubMed
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PURPOSE: Metastasis-associated in colon cancer-1 (MACC1) is a newly identified gene that plays an important role in cancer progression and metastasis. MACC1 has important functions in the differentiation, invasion, and metastasis of nonsmall cell lung cancer (NSCLC). However, the value of circulating MACC1 as a potential diagnostic and prognostic biomarker for NSCLC remains unknown.
METHODS: Plasma MACC1 mRNA levels were examined in 272 patients with NSCLC, 61 with benign lung disease, and 80 healthy volunteers using reverse transcription quantitative real-time polymerase chain reaction.
RESULTS: MACC1 was more highly expressed in NSCLC patients than in patients with benign disease (P < 0.001) or in healthy volunteers (P < 0.001). High MACC1 expression was significantly associated with NSCLC stage (P = 0.013) and lymph node metastasis (P = 0.016). The area under the receiver operating characteristic curve was 0.766, and the optimal cutoff value was 0.105, providing a sensitivity of 71.4 % and a specificity of 89.1 %. The diagnostic capability of circulating MACC1 mRNA was higher than that of carcinoembryonic antigen (P = 0.025) or cytokeratin-19 (P = 0.010). Furthermore, high MACC1 expression was associated with poor overall survival (OS) and disease-free survival (DFS) and predicted poor survival in NSCLC patients. Consequently, MACC1 mRNA was an independent prognostic factor of OS and DFS.
CONCLUSION: We concluded that circulating MACC1 mRNA represents a potential noninvasive, diagnostic and prognostic marker for NSCLC.
Li HF, Liu YQ, Shen ZJ, et al.Downregulation of MACC1 inhibits invasion, migration and proliferation, attenuates cisplatin resistance and induces apoptosis in tongue squamous cell carcinoma.
Oncol Rep. 2015; 33(2):651-60 [PubMed
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The aim of the present study was to investigate the expression and function of metastasis-associated in colon cancer 1 (MACC1) in tongue squamous cell carcinoma (TSCC) and its relationship with the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147). Levels of MACC1 and EMMPRIN expression were analyzed in 65 paraffin‑embedded tissue specimens of TSCC and in the adjacent non-cancerous tissues using immunohistochemistry (IHC). MACC1 expression was highly associated with lymphatic metastasis and EMMPRIN expression. Overexpression of MACC1 was significantly correlated with poor overall patient survival. A small interfering RNA (siRNA) was delivered into TSCCA cells to downregulate MACC1 expression. The CCK-8 assay showed that TSCCA cell proliferation was markedly reduced and that cisplatin resistance was attenuated. The suppression of MACC1 promoted the apoptosis of the TSCCA cell line. A Transwell experiment demonstrated that the migration and invasion abilities of the TSCCA cells were extremely downregulated. An ELISA experiment and western blotting revealed that the secretion of urokinase-type plasminogen activator system (uPA) in the supernatant of the culture medium and uPA expression were significantly reduced. Experiments revealed that the secretion of metalloproteinase 2 (MMP2) in the supernatant of the culture medium and MMP2 expression were not affected. MACC1 may serve as a novel biomarker and therapeutic target for TSCC.
Wang G, Fu Z, Li DMACC1 overexpression and survival in solid tumors: a meta-analysis.
Tumour Biol. 2015; 36(2):1055-65 [PubMed
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Metastasis associated in colon cancer-1 (MACC1) is a newly identified oncogene, and increasing evidence has suggested that its overexpression is associated with the development and progression in many tumors. Here, we perform a meta-analysis to assess the relationship between MACC1 overexpression and survival in solid tumors. Eligible studies were searched in Embase, PubMed, and Web of Science databases up to May 2014. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to estimate the impact of MACC1 overexpression on survival using a random-effect model. A total of 20 eligible studies dealing with various tumors were included in the analysis: 17 were dealing with overall survival (OS), 7 were with relapse-free survival (RFS), and 3 were with disease-free survival (DFS). Combined results suggested a strong link between the high MACC1 expression and the poor overall survival (HR 2.11, 95% CI 1.59-2.80, P < 0.001). For relapse-free survival, overexpressed MACC1 was also a significant predictor, with a combined HR of 2.22 (95% CI 1.80-2.74, P < 0.001). Data from the three studies were combined to show that MACC1 overexpression had also an unfavorable impact on disease-free survival (HR 2.94, 95% CI 1.60-5.38, P < 0.001). Publication bias was not significant. The present meta-analysis showed that overexpression of MACC1 was significantly associated with poorer survival in solid tumors.
Lin L, Huang H, Liao W, et al.MACC1 supports human gastric cancer growth under metabolic stress by enhancing the Warburg effect.
Oncogene. 2015; 34(21):2700-10 [PubMed
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Cancer cells mainly metabolize by glycolysis (the Warburg effect) and are better adapted to resist metabolic stress. Metastasis-associated in colon cancer-1 (MACC1) is an oncogene promoting gastric cancer (GC) growth and metastasis, and its expression positively correlates with GC progression. However, it is unknown why MACC1 elevates with GC progression and what is its role in cancer metabolism. In this study, we discovered that MACC1 expression was significantly upregulated via adenosine monophosphate-activated protein kinase signaling in response to glucose deprivation-induced metabolic stress. Clinical observation demonstrates that MACC1 expression was higher in advanced stage GC. MACC1 expression was proved to be positively correlated with the maximum standardized uptake value of (18)F-deoxyglucose in the patients, and MACC1 enhanced (18)F-deoxyglucose uptake in GC cells and the xenografts. The underlying mechanism was that MACC1 promoted the Warburg effect by upregulating the activities and expressions of a series of glycolytic enzymes, including hexokinase, pyruvate dehydrogenase kinase and lactate dehydrogenase, in GC cells. This metabolic shift enhanced cell viability and resistance to apoptosis by facilitating ATP generation, reducing the reactive oxygen species production and stabilizing the mitochondrial membrane potential. In contrast, MACC1-silenced or the Warburg effect-blocked GC cells were more vulnerable to metabolic stress. In conclusion, metabolic stress is one of the mechanisms that elevate MACC1 expression in GC, and MACC1 upregulation compensatively ensures GC growth against metabolic stress by facilitating the Warburg effect.
Here we confirmed that metastasis-associated in colon cancer 1 (MACC1) and β-catenin expression were higher in colorectal cancer (CRC) cells and tissues than those in normal colonic epithelial cell line and adjacent non-tumour colorectal mucosa (ANM) tissues, respectively. MACC1 expression was significantly related to histological differentiation (p<0.001), UICC stage (p=0.029), T classification (p=0.017), and N classification (p=0.023). Cox regression analysis demonstrated that high MACC1/abnormal β-catenin expression was the strongest independent prognostic indicator for reduced overall survival in CRC patients. Significant positive correlation between MACC1 expression and abnormal β-catenin expression was found in CRC tissues. MACC1 knockdown dramatically inhibited cellular proliferation, migration, invasion, colony formation, and tumorigenesis, both in vitro and in vivo, but induced apoptosis in CRC cells. Further MACC1 over-expression increased Met, β-catenin, and its downstream genes including c-Myc, cyclin D1, and MMP9 expression, and its upstream gene phos-GSK3β (Ser9) expression. In addition, MACC1 increased vimentin and suppressed E-cadherin in HCT116 cells. Silencing of MACC1 reversed all these changes. Our results firstly suggest that MACC1 plays an important role in carcinogenesis and progression of CRC through β-catenin signaling pathway and mesenchymal-epithelial transition.
Metastasis-associated in colon cancer 1 (MACC1) has recently been identified as a novel independent prognostic indicator for metastasis occurrence, overall survival and cancer-free survival for patients with colon cancer and other solid tumors. In this study, we investigated the role of MACC1 in the development and progression of renal pelvis carcinoma, a form of upper tract urothelial carcinomas. MACC1 protein has been found in the cytoplasm as well as in the nucleus of the transitional epithelial cells of the normal renal pelvis in immunohistochemical (IHC) assays. Quantitative IHC examinations revealed that MACC1 abnormal abundance in cancerous tissues might represent a biological indicator clinically suggestive of tumor malignancy in the renal pelvis. Furthermore, investigation of the association of MACC1 protein levels with clinicopathological parameters in this study has suggested a correlation of MACC1 expression with tumor-node-metastasis stage and histopathological grade of patients with renal pelvis carcinoma, with elevated MACC1 protein levels frequently associated with higher aggressiveness of the disease. Moreover, both disease-free survival and overall survival for the patients in the high MACC1 expression group were significantly lower than those in the low expression group. Multivariate analysis with a Cox proportional-hazards model suggested that MACC1 is indeed an independent prognostic indicator of overall survival and cancer-free survival for patients with renal pelvis carcinoma. Thus, MACC1 may represent a promising prognostic biomarker candidate, as well as a potential therapeutic target for this disease.
Muendlein A, Hubalek M, Geller-Rhomberg S, et al.Significant survival impact of MACC1 polymorphisms in HER2 positive breast cancer patients.
Eur J Cancer. 2014; 50(12):2134-41 [PubMed
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BACKGROUND: Deregulation of hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (MET) signalling has been associated with poor clinical outcome in breast cancer and other cancers. The recently discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Potential links between genetic variants of the MACC1 gene and survival in breast cancer patients are unknown. In the present study, we therefore aimed to investigate the influence of MACC1 polymorphisms on event-free and overall survival in patients with human epidermal growth factor 2 (HER2)-positive breast cancer.
METHODS: The present study included 164 consecutive white patients with HER2-positive breast cancer. Three MACC1 polymorphisms, rs1990172, rs975263 and rs3735615, already associated with cancer prognosis or with potential functional effects, were genotyped by the 5' nuclease assay.
RESULTS: Multivariate Cox regression analysis adjusted for age and tumour stage showed increased risk for progression or death for carriers of the rare allele (G-allele) of single nucleotide polymorphism (SNP) rs1990172 (hazard ratios (HR) = 2.26; p = 0.004 and HR = 3.13; p = 0.001 for event-free survival and overall survival, respectively). In addition, we were able to demonstrate an adverse effect on cancer prognosis for carriers of the rare allele (T-allele) of SNP rs975263 (HR = 2.17; p = 0.007 and HR = 2.80; p = 0.003 for event-free survival and overall survival, respectively). The rare allele (C-allele) of SNP rs3735615 showed a significant protective impact on event-free survival as well as overall survival (HR = 0.25; p = 0.001, and HR = 0.16; p = 0.001, respectively).
CONCLUSIONS: This study provides first evidence that MACC1 polymorphisms are associated with clinical outcome for HER2-positive breast cancer patients. Further studies are warranted to validate these findings.
Fujinaga T, Kumamaru W, Sugiura T, et al.Biological characterization and analysis of metastasis-related genes in cell lines derived from the primary lesion and lymph node metastasis of a squamous cell carcinoma arising in the mandibular gingiva.
Int J Oncol. 2014; 44(5):1614-24 [PubMed
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Controlling metastatic lesions is an important part of improving cancer prognosis, in addition to controlling the primary lesion. There have been numerous histological studies on primary and metastatic lesions, but little basic research has been performed using cell lines from primary and metastatic lesions belonging to the same patient. In this study, we successfully established a cell line derived from lower gingival carcinoma (WK2) as well as a line derived from secondary cervical lymph node metastasis (WK3F) through primary cultures of tissue from a patient with oral squamous cell carcinoma. We then investigated the biological characteristics of the cancer cell lines from these primary and metastatic lesions and analyzed metastasis-related genes. Comparison of the biological characteristics in vitro showed that WK3F had higher cell proliferation ability and shorter cell doubling time than WK2. WK3F also had increased cell migratory ability and higher invasive and self-replication abilities. Heterotransplantation into nude mice resulted in high tumor formation rates in the tongue and high metastasis rates in the cervical lymph nodes. Changes in WK2 and WK3F gene expression were then comprehensively analyzed using microarrays. Genes with increased expression in WK3F compared to WK2 were extracted when the Z-score was ≥2.0 and the ratio was ≥5.0, while genes with reduced expression in WK3F compared to WK2 were extracted when the Z-score was ≤-2.0 and the ratio was ≤0.2; differences were found in 604 genes. From these, MAGEC1 (88.0-fold), MMP-7 (18.6-fold), SNAI1 (6.6-fold), MACC1 (6.2-fold), and HTRA1 (0.012-fold) were selected as metastasis-related candidate genes. The results suggest that these molecules could be important for clarifying the mechanisms that regulate metastasis and provide new therapeutic targets for inhibiting tumor invasion.